The ultimate aim of this program is to decrease the high mortality of rodent-borne viral zoonoses (HPS and Bolivian hemorrhagic fever) in the Americas. Our interdisciplinary team will combine the capability of predicting environmental events that favor outbreaks of zoonotic disease, with the capability of early diagnosis and targeted therapy based on a sound knowledge of immumnopathogenesis and antiviral therapy. The first Project will develop a capability to predict bursts of SNV infection in rodent populations, using longitudinal studies of rodent abundance, density and infection rate, coupled with experimentally- constructed plots in which rodent density is artificially manipulated. It will test the hypothesis that certain habitats provide a nidus of persistent rodent infection, from which adjacent habitats are infected by spillover when climatic conditions favor increase rodent density and infection. GIS-based data (Core A) will translate small-scale measures of rodent density and SNV prevalence into large-scale markers to predict increased risk of human infection. Project will extend these ecologic studies to Machupo virus infection of rodents in Bolivia, and will test the hypothesis that Bolivian hemorrhagic fever outbreaks are restricted to a fraction of the entire range of Calomys callosus host, because, like hantaviruses, selected habitats favor persistent rodent infection that spills over into human hosts after environmental and human disturbances. The third project examines the epitope specificity and cytokine secretion patterns of T cell clones and T cells from acute HPS patients and will test the hypothesis that the massive capillary leak is due to excessive T cell stimulation. It will yield alternative therapies to abort the cytokine storm and reduce mortality.